This invention relates to a method for treating certain allergic diseases, primarily those of the upper respiratory tract.
The immune system is capable of responding in a number of effective ways to protect the body from harmful agents such as bacteria, viruses or toxins. In some genetically susceptible individuals who are allergic, it responds inappropriately to innocuous substances. Atopic allergy is expressed as a type I hypersensitivity reaction (Gell and Coombs classification) in which "reaginic" antibodies, usually of the Immunoglobulin E (I.sub.g E) class, when triggered by environmental allergens, release chemical mediators such as histamine from the specialized cells to which they are attached. Some of these specialized cells, called "mast" cells, are distributed in the mucous membranes of the upper respiratory system and the gut and also in the skin. Mediators released from tissue mast cells act locally on target organs to produce the distressing symptomatology of hay fever, asthma, food intolerance, or localized itching of the skin (urticaria).
Approximately 10% of the United States population suffers from atopic allergy. Most of the allergens which provoke the hypersensitivity reaction are airborne pollens, animal dander, and common dust, all of which are most likely to enter the body by inhalation to lodge in the respiratory tract. For this reason, allergic rhinitis and allergic bronchial asthma are the most common diseases of their class.
Allergic rhinitis may be seasonal or perennial depending on the causative allergen. Seasonal allergic rhinitis (hay fever) is commonly caused by plant pollens; perennial allergic rhinitis may be caused by agents such as house dust or animal dander. The characteristic feature of allergic rhinitis is the pale edematous swelling of the mucosa of the upper respiratory tract, which may cause obstruction of the nasal passages, sinus ostium and eustachian tubes. Laryngeal edema may also result in hoarseness. Commonly the conjunctiva are swollen and the eyes and nose have a watery discharge.
About one third of the cases of bronchial asthma are allergic in nature, and allergy is a contributing factor in another third. These cases are often described as "extrinsic" asthma. The characteristic feature of bronchial asthma is constriction of bronchial smooth muscle which makes it difficult for the sufferer to move air through the bronchial passages, particularly during exhalation. This constriction in allergic asthma is caused by a response of autonomic nervous system receptors in the bronchial mucosa to the release of histamine and other chemical mediators in response to the allergen stimulation described above.
Drugs can act non-specifically to prevent or relieve the symptoms of hypersensitivity reactions. Cromolyn sodium prevents the release of chemical mediators from tissue mast cells in asthmatic patients, and antihistamine drops are used to competitively inhibit this mediator effectively after its release and so alleviate the symptoms of rhinitis. Beta-adrenergic agents are used as bronchodilators for asthma, and steroids relieve the bronchial constriction by an unknown mechanism of action.
Specific treatment of atopic allergy requires prior identification of the offending allergen. Skin testing, in which a small quantity of allergen scratched or injected into the skin produces a characteristic wheal and flare in an allergic individual, has historically been the method of choice in allergen identification; however, it is now being replaced by more convenient in vitro immunoassays for specific I.sub.g E antibodies. Both skin testing and specific I.sub.g E assays are useful when the patient is sensitive to a common allergen, but in cases where the allergen is uncommon, the search to identify it by either procedure may be tedious, expensive, and in some instances, impossible.
If the specific allergen can be identified, future allergic episodes can be prevented by eliminating it from the patient's environment. If this is restrictive or not possible, and the allergy is incapacitating, the patient may elect to be specifically desensitized to the allergen by immunotherapy. To achieve this, small amounts of extracted allergen and/or chemically denatured allergen (allergoid) are injected into the patient repeatedly over a period of time. The allergoid should be incapable of stimulating I.sub.g E production but instead stimulate a "blocking" I.sub.g G. I.sub.g G binds allergen in a soluble complex and thus prevents its interaction with I.sub.g E on the surface of tissue mast cells. Where it is successful, this alteration of the immerse response produces long-lasting relief. Desensitization is less feasible when, as often is the case, a patient is sensitive to multiple allergens. Also, it carries the risk of triggering an allergic incident, requires an extended period of time to be effective, and frequently fails altogether to protect against the allergic response.
A desirable treatment for atopic allergy would be one that could achieve the long lasting benefits of desensitization immunotherapy, and yet like the drug approach, not require an identification of specific allergen(s).
A non-specific immunotherapy for atopic allergy was proposed by R. Hamburger in 1975 (Science 189 389). In this approach, it was suggested that a synthetic pentapeptide, identical to that region of the I.sub.g E molecule which binds to the I.sub.g E receptor on the mast cell surface, would be injected into the patient. This peptide could then block I.sub.g E attachment by competing for the binding site on mast cell surfaces, and thus prevent the release of chemical mediators triggered by allergen. Successful results have been reported when the serum of allergic patients treated with appropriate pentapeptide showed decreased I.sub.g E level as measured by the Prausnitz-Kustner reaction; however, this mode of therapy is not yet available.
Vitamin B.sub.12 is a specific therapy only in pernicious anemia or in specific nutritional deficiency; however, it is commonly used as a non-specific, supportive therapy for patients recovering from infections, complaining of fatigue, or experiencing physiological stress from various and diverse causes. Not surprisingly, it has been similarly administered to patients suffering from asthma. In a few cases, these patients experienced short term relief from their symptoms together with subjective qualitative feelings of well-being; but overall, the efficacy of vitamin B.sub.12 therapy as a general remedy for atopic allergy is indeterminate.
In 1952, Caruselli reported a one year experimental use of vitamin B.sub.12 injections in attempting to relieve the symptoms of eight asthmatic patients who were refractory to conventional drugs. He reports that seven of these obtained temporary symptomatic relief after five to twenty days of treatment. The other patient showed no improvement after three months of treatment with 30 .mu.g of vitamin B.sub.12 per day.
Caruselli's study was defective because it reports no control group studied which could provide data on the number of patients who improved without treatment. Further, the study does not indicate whether the asthma cases treated were of the extrinsic or intrinsic type, and if extrinsic, whether the underlying allergy was seasonal, in which case symptoms could disappear spontaneously; nor does he indicate that other medication was discontinued during the B.sub.12 treatment. Finally, the study is ambiguous and inconclusive because the patients were not followed long enough to determine if the symptomatic relief persisted beyond the period of treatment.
In 1959, Trampiz undertook a clinical study of Vitamin B.sub.12 therapy in a group of 14 adults and 50 children. Again, there were no controls, no classification into disease categories, and no long-term follow up. The dosages between the adult and child groups were disproportionate, with the children receiving 30 .mu.g per day for 20 days and the adults 4 to 5 mg. Of the 64 patients treated, 42 showed some degree of improvement, and the remainder were unresponsive. All of those who responded were children who were poorly nourished at the beginning of treatment, and their symptomatic relief occurred in the context of better appetite and improved nutrition. The adults, none of whom enjoyed symptomatic relief from asthma, gained weight and felt better.
It is accordingly an object of this invention to provide a method for treating atopic allergy by selecting from the patient population a group of individuals likely to benefit from Vitamin B.sub.12 therapy, and applying such therapy to provide these patients with long term relief from these diseases.
It is a further object of this invention to provide a method for treating atopic allergy non-specifically, that is without the need to identify a causative antigen, by using an immunotherapy approach which provides long-term relief comparable to that of specific desensitization.